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Genome Editing – ethical questions take on a new dimension

Genome Editing – ethical questions take on a new dimension

In recent decades, intensive research efforts in molecular-genetic basic research have specifically developed a new method to change DNA (deoxyribonucleic acid). Clustered Regularly Interspaced Short Palindromic Repeats as we know as CRISPR, it was first described in 2012 by a working group led by Emmanuelle Charpentier and Jennifer Doudna. It was declared "Break-through of the Year" in 2015 by the scientific journal Science 2015 (1). 

The revolutionary technology promises extraordinary opportunities in the field of gene therapy to develop new treatment options. A large number of genetically determined (condonation)diseases that are triggered by mutations in genes are still considered to be incurable. Parkinson's, Alzheimer's, amyotrophic lateral sclerosis (ALS), cancer, and even viral infections such as HIV are among the diseases that could be treated by editing genes (2-5). 

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The CRISPR / Cas9 method also opens up new opportunities for plant breeding, insect control, and reproductive medicine. At the latest, when gene scissors are used in these areas, ethical questions take on a new dimension. The use of the method to achieve a therapeutic effect is less criticized than changing the genetic makeup of embryos to create a genetically modified embryo. Ethics committees play a significant role in the approval of new studies and medicines. In many countries, such as Japan, China, and the USA, experiments with embryos are less strict than in Europe. The question is who is responsible for the risks of developing new gene therapies and who is ultimately the commercial profiteer. Understanding the basic principle of the new genome editing method is intended to simplify discussing the associated risks.

How the CRISPR / Cas9 technology works

As is well known, DNA determines the basic building block of all life. It determines the structure of organisms and thus also their appearance, but also controls various biochemical processes in the body. In the case of genetic diseases, errors in the base sequence of the DNA occur, among other things, due to mutations. Mutations are permanent changes in genetic material passed on to daughter cells from the original cell in which they arise. If these errors in the DNA could be identified and repaired in a targeted manner, new opportunities would open up in treating genetic diseases. Genome editing is based on this basic principle. DNA is to be cut open and modified in a targeted manner in the area of a gene of interest. Bacteria have already developed this mechanism in evolution to defend themselves against pathogens of viral origin, so it is a natural defense mechanism. This was adopted explicitly over decades of intensive research and adapted to the human genome; the new technology became known worldwide as CRISPR / Cas9. The abbreviation CRISPR refers to specific gene sequences in bacteria. Cas9 is the name of a protein with which it is possible to locate gene sequences selectively. However, the mechanism is not just limited to bacteria. In 2012, researchers in the USA discovered that this mechanism works in all organisms to cut DNA at any point.

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The specialty of the Cas9 protein is that it has a short gene sequence that determines where the scissors start. This gene sequence can be changed at will and thus used by scientists to target the desired DNA in the organism. If the matching counterpart, i.e., the complementary DNA, is found in a cell, Cas9 connects to it. In the next step, the endonuclease activity of the Cas9 protein cuts the DNA at precisely the place where it has laid down. This means that the genome can be cut at a specific point. This is where the term gene scissors come from, which is often used for this technology. An advantage compared to other similar technologies is that the method remains inexpensive due to its simplicity in its application. In addition, it is exact, so few off-target effects result in the risk of unwanted changes in the genetic makeup. In this way, genes can be switched off and repaired or modified in a targeted manner through the subsequent insertion of new sequences. A repair can be repaired through the natural mechanism of non-homologous end-joining by joining free DNA ends together. Another possibility is to insert a repair template and thus replace the cut-out DNA sequence with any new series (6, 7).

Versatile areas of application through simple mechanisms

The technology can be used in many areas because any DNA sequences can be exchanged on the Cas9 protein. In addition to cutting out defective gene sequences responsible for diseases, targeted crops can also be used, and animals are genetically modified and thus made more productive and more resilient. Nevertheless, the research on CRISPR / Cas9 is still in its infancy. Although it is more precise than other methods, it is still impossible to achieve 100% accuracy, which means that unwanted changes can still occur, and the consequences of the intervention cannot be assessed. In addition, the technology is a non-reversible method. Changes that have been made and do not show the desired effect cannot be undone. It is also not yet known how the changed genes can affect subsequent generations. Thus, there is still a long way to go before incurable diseases are cured, or the desired designer baby is produced.

Nevertheless, the opportunities offered by CRISPR / Cas9 are pointed out from many sides, and the risks need to be considered and assessed. The question arises of who takes on the risks and which areas of application are ethically justifiable. Modern technologies in medicine are often, as many other examples show, only accessible to the elite class of society, which means that the development of a 2-class medicine is further promoted. Another problem is the responsible handling of genome data. There are many unanswered questions, particularly about ethics and responsibility, that arise with this new technology.

What is ethical?

Both the media and specialist societies have been discussing what is ethically justifiable for some time. Opinions differ as to what genome editing should be used for. Intervening in the genetic makeup of embryos to create genetically modified embryos that correspond to an ideal is particularly criticized. Here, however, decisions are made differently at the national level. In Germany, it is forbidden to intervene in the genetic material of an embryo. There is no worldwide ban on this. In Japan, China, and the USA, for example, there are no strict regulations. These differences in legislation can result in the migration of research institutes in the field of new technologies and medical tourism, i.e., cross-border use of medical treatments.

Worldwide criticism rose after media coverage of the birth of genetically modified twins in China in 2018 (8). The Chinese biophysicist, He Jiankui, was the first to perform genetic engineering in the germline of a human embryo. Whether this is true is still unclear, as no official publication has been published. According to He, embryos were genetically modified after artificial insemination with CRISP / Cas9. He allegedly deactivated a receptor in the children's genome that is required for HIV infection. This is said to have made the children resistant to the HI virus and thus no longer become infected. The method has been used on seven couples, all of whose fathers were HIV positive. Finally, the birth of twins with this resistance is said to have been successful (8).

It is not the first time that genetic tools have been used in medicine. According to a press release from UCSF Benioff Children's Hospital in the USA, a patient with the metabolic disease Hunter's disease was treated with gene therapy based on gene scissors technology as part of a clinical study (9). The difference to the above case is that the babies were changed as embryos. 

A gene change in the embryo means that it can later be found in all cells. So also, in egg and sperm cells, this means that the changed effect is inherited when reproduced again. The twins from China pass on the change and supposed resistance to the HI virus to their offspring. The focus of ethical discussions is which properties of organisms can be changed and passed on in this way. Changes can be made to people that they cannot yet agree to. Technologies emerge whereby neither the embryos nor subsequent generations have a say. Another view is that a change in the genetic makeup is a natural process and continues to occur in evolution through natural selection. A shift in egg and sperm cells is also essentially regular. Targeted intervention in the genetic material of embryos can be justifiable in the case of two parents with hereditary congenital disabilities.

Other fundamental ethical questions determine social discourse. Concerning food and feed, the question arises as to whether natural, unmodified foods are safer. The question is whether naturalness is an adequate criterion for health and whether consumers should have the freedom of choice to decide individually to consume genetically modified foods. New techniques in plant breeding have been in use for a long time. The so-called GM plants can no longer be distinguished from traditional breeding products that have emerged over decades. The new methods mean that specific locations of the genetic material can be targeted, and a precise change is possible quickly. This can result in plants that are more resistant to heat, drought, and salt exposure. Because of the changing global climate, this can be an advantage for a comprehensive supply of the growing world population. This represents a new opportunity for agriculture, especially in regions with poor environmental conditions. 

Healthier Food

In the USA and Canada, the cultivation of GM plants has been permitted since 2014. The plants are not only made more productive and more resistant but also healthier. One example is the potato. It is known that when French fries are made, the byproduct of frying is acrylamide. This compound is considered to be potentially carcinogenic. The new GM potatoes produce up to 75 percent fewer acrylamides during frying. A significant benefit for consumers that would not have been possible through breeding alone (10).

The legal framework lags the research

Since it has been possible to imitate processes in the laboratory, of course, it is no longer possible to determine which methods were used to create the mutations. The change of a cultured organism can no longer be distinguished from that of an organism that has been changed by "genome editing." This makes it challenging to define the legal framework for the authorization of genetically modified organisms. There are currently no globally applicable regulations. There is no question that laws will be needed to deal with organisms and the dangers they pose. Further discussions, which ideally lead to global rules, are desirable in this area. Such laws could counteract a further development of the two-class society, especially in the field of medicine.

Written by Göktug Önyer 

1 Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science (New York, N.Y.), 337(6096), 816–821. doi:10.1126/science.1225829 

2 Brenner D. et al. Hot-spot KIF5A mutations cause familial ALS. Brain. 2018. Mar 1;141(3):688-697. doi:10.1093/brain/awx370

3 McCain J. (2005). The future of gene therapy. Biotechnology Healthcare, 2(3), 52–60.

4 Xu, W. et al. (2019), CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukemia, N Engl J Med 2019; 381:1240-1247, DOI: 10.1056/NEJMoa1817426

5 Sánchez-Rivera, F., Jacks, T. Applications of the CRISPR–Cas9 system in cancer biology. Nat Rev Cancer 15, 387–393 (2015) doi:10.1038/nrc3950

6 Cho SW, Kim S, Kim JM. et al. Targeted genome engineering in human cells with the Cas9 RNA-guided endonuclease. Nat Biotechnol 2013; 31: 230-232

7 Cong L, Ran FA, Cox D. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 2013; 339: 819-823

8 Marilyn Marchione, Chinese Researcher Claims First Gene-Edited Babies, Associated Press (Nov 26, 2018) https://www.apnews.com/4997bb7aa36c45449b488e19ac83e86d (accessed Jan 11, 2019).

9 Sheridan, C. Sangamo's landmark genome editing trial gets a mixed reception. Nat Biotechnol 36, 907–908 (2018) doi:10.1038/nbt1018-907

10 Araki, M. und Tetsuya, I. (2015): Towards social acceptance of plant breeding by genome editing. In: Trends Plant Science 2015, Vol. 20 (3), März 2015, doi: 10.1016/j.tplants.2015.01.010.

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